Crystalline polymorphic form of ulipristal acetate

ABSTRACT

A novel crystalline polymorphic form of ulipristal acetate useful as an agent for preventing and/or treating uterine leiomyoma and as a contraceptive, and a process for producing the crystalline polymorphic form are provided. The novel crystalline polymorphic form of ulipristal acetate is obtained by dissolving an isopropanol-solvated crystal of ulipristal acetate in a mixed solvent containing ethanol and water, and crystallizing an ulipristal acetate from the solution without addition of a seed crystal to the solution.

TECHNICAL FIELD

The present invention relates to a novel crystalline polymorphic form ofulipristal acetate, which is useful as a contraception or as an agentfor preventing and/or treating uterine leiomyoma or other agents, andrelates to a process for producing the crystalline polymorphic form.

BACKGROUND ART

Ulipristal acetate[17alpha-acetoxy-11beta-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione;hereinafter, may be referred to as UPA], which is a steroid compoundpossessing antiprogestational activity and antiglucocorticoidalactivity, is on the market as an emergency contraceptive drug in theUnited States and Europe.

As a crystalline ulipristal acetate, for example, Japan Patent No.2953725 publication (JP-2953725B, PTL 1) discloses a crystalline UPAhaving a melting point at a temperature of 118 to 121° C. obtained byrecrystallization from a mixed solvent of methanol and water. WO96/30390publication (PTL 2) discloses a crystalline UPA having a melting pointat a temperature of 183 to 185° C. obtained by crystallization fromdiethyl ether. Japanese Patent Application Laid-Open Publication No.2006-519255 (JP-2006-519255A, PTL 3) discloses a crystalline UPA havinga melting point at a temperature of 183 to 185° C. obtained byrecrystallization from an ethanol aqueous solution (90%). JapanesePatent Application Laid-Open Publication No. 2006-515869(JP-2006-515869A, PTL 4) discloses a crystalline UPA having a meltingpoint of 189° C. obtained by recrystallization from an ethanol/water(80/20) mixed solvent. Japanese Patent Application Laid-Open PublicationNo. 2009-539964 (JP-2009-539964A, PTL 5) discloses a crystalline UPAhaving a melting point at a temperature of 184 to 186° C. obtained byrecrystallization from a mixed solvent of ethanol (230 mL) and water(260 mL).

There is still a need for new crystalline forms of ulipristal acetatehaving improved solubility and/or improved bioavailability.

CITATION LIST Patent Literature

PTL 1: JP-2953725B (Claims, Examples)

PTL 2: WO96/30390 publication (Claims, Examples)

PTL 3: JP-2006-519255A (Claims, Examples)

PTL 4: JP-2006-515869A (Claims, Examples)

PTL 5: JP-2009-539964A (Claims, Examples)

SUMMARY OF INVENTION Technical Problem

It is therefore an object of the present invention to provide a novelcrystalline polymorphic form of ulipristal acetate, which is useful asan agent for preventing and/or treating uterine leiomyoma or otheragents, and to provide a process for producing the crystallinepolymorphic form. The novel crystalline form of ulipristal acetate maybe useful as a contraceptive, e.g., an emergency contraceptive. Thenovel crystalline form of the invention may be also useful as a drug,for instance for treating and/or preventing a gynecological disordersuch as uterine fibroids or leiomyoma, endometriosis, uterine bleedings,pain associated with dislocation of endometrium and the like.

It is another object of the present invention to provide a novelcrystalline polymorphic form of ulipristal acetate having excellentcharacteristics (such as solubility, stability, absorption, improvedbioavailability), and to provide a process for producing the crystallinepolymorphic form.

Solution to Problem

The inventors of the present invention made extensive studies to achievethe above objects and finally found that a wide variety of crystals canbe produced by adjusting crystallization conditions of an ulipristalacetate (for example, a crystallization solvent, a method for generatingsupersaturation, and a drying method); that among these crystals thereis a novel crystalline form different in structure from a conventionalcrystalline form; that the novel crystalline form can be obtained as asingle crystalline form without substantial coexistence with othercrystalline forms by crystallization under a specific crystallizationcondition; that an ulipristal acetate substance containing the novelcrystalline form has excellent characteristics (e.g., solubility,stability, and absorption) and can improve bioavailability. Acrystalline polymorphic form C of ulipristal acetate of the inventionmay enable to decrease the dosage of ulipristal acetate to administer tothe patient so as to obtain the requested or required therapeutic orcontraceptive effect. The present invention was accomplished based onthe above findings.

A first aspect of the invention is a crystalline form C (crystal C) ofulipristal acetate having an X-ray powder diffraction pattern comprisingdiffraction peaks at the following diffraction 2theta angles: 9.0±0.2°,9.3±0.2°, 10.8±0.2°, 11.5±0.2°, 12.2±0.2°, 13.1±0.2°, 14.3±0.2°,15.6±0.2°, 15.7±0.2°, 15.9±0.2°, 16.6±0.2°, 17.6±0.2°, 17.9±0.2°,18.9±0.2°, 19.3±0.2°, and 23.8±0.2°.

In some embodiments, said crystalline form C has an X-ray powderdiffraction pattern as depicted in FIG. 1 or as described in Table 1.Preferably, the X-ray powder diffraction pattern is obtained with adiffractometer equipped with a Cu K alpha-1 radiation source.

In some additional or other embodiments, the crystalline form C of theinvention has a differential scanning calorimetry spectrum, whichexhibits an endothermic peak of about 135 to 145° C. The crystallineform C of the invention may further have a differential scanningcalorimetry spectrum as depicted in FIG. 2.

Another aspect of the invention is an ulipristal acetate substancecomprising the crystalline form C.

It is sufficient that the ulipristal acetate substance (also calledherein ‘ulipristal acetate mixture’) contains the crystallinepolymorphic form C. The ulipristal acetate substance may further containa different crystalline polymorphic form (a crystalline polymorphic formdifferent from the crystalline polymorphic form C) of ulipristal acetate[for example, a crystalline polymorphic form A (crystal A), acrystalline polymorphic form B (crystal B)]. The crystalline polymorphicform A (or the ulipristal acetate substance containing the crystallinepolymorphic form A) has an X-ray powder diffraction pattern comprisingdiffraction peaks at the following diffraction 2theta angles:

-   -   9.2±0.2°, 11.4±0.2°, 11.7±0.2°, 12.0±0.2°, 15.2±0.2°, 17.0±0.2°,        17.2±0.2°, and 24.4±0.2°.

The crystalline polymorphic form B (or the ulipristal acetate substancecontaining the crystalline polymorphic form B) has an X-ray powderdiffraction pattern comprising diffraction peaks at the followingdiffraction 2theta angles:

-   -   6.4±0.2°, 8.4±0.2°, 9.4±0.2°, 9.6±0.2°, 11.8±0.2°, 12.8±0.2°,        15.3±0.2°, 16.7±0.2°, 17.5±0.2°, 18.6±0.2°, 19.3±0.2°,        21.0±0.2°, and 25.5±0.2°.

The ratio of the crystalline polymorphic form C relative to thedifferent crystalline polymorphic form (for example, the crystallinepolymorphic form A, or the crystalline polymorphic form B) may be about0.5/99.5 to 99.5/0.5 in a weight ratio of the former/the latter. Theabove-mentioned weight ratio can be determined based on the relationshipbetween weight ratio and diffraction peak intensities (the height fromthe baseline of diffraction peak) by measuring the diffraction peakintensities of a reference ulipristal acetate substance containing thecrystalline polymorphic form C and other form in a predetermined weightratio.

The instant invention further relates to a pharmaceutical compositioncomprising the polymorphic form C or an ulipristal acetate substanceaccording to the invention, and a pharmaceutically acceptable excipient.The pharmaceutical composition may be used as a contraceptive, e.g., asan emergency contraceptive. Alternatively, the pharmaceuticalcomposition of the invention may be used for treating and/or preventinga gynecological disorder such as uterine fibroids, endometriosis,uterine bleedings, pain associated with dislocation of endometrium andthe like.

An additional aspect of the invention is a method for producing acrystalline polymorphic form C or an ulipristal acetate substance of theinvention.

The process for producing the crystalline polymorphic form C or theulipristal acetate substance of the present invention comprisesdissolving an isopropanol-solvated crystal of ulipristal acetate in amixed solvent containing ethanol and water, and crystallizing anulipristal acetate from the solution. In this step, it is preferablethat the crystallization of the ulipristal acetate be carried outwithout addition of a seed crystal to the solution.

Throughout this description, the diffraction angle having a peak (or thepeak angle) includes a variable range of

±0.2°.

In the same crystalline form, even if a plurality of peak angles(including a variable range) formally overlaps with each other, each ofthe peak angles is independent in measurement. For example, thecrystalline polymorphic form C has diffraction peaks at

9.0±0.2° and 9.3±0.2°,

and the angle of 9.1 to 9.2° belongs to these two ranges. In this case,it means that there are two different independent peaks at differentangles; one peak at 9.0±0.2° and the other at 9.3±0.2°.

Advantageous Effects of Invention

The ulipristal acetate substance and the polymorphic form C of thepresent invention have a higher solubility and more excellent stabilityand absorption compared with a conventional crystalline form, and canimprove bioavailability. Moreover, the ulipristal acetate substance andthe polymorphic form C of the present invention are useful as an agentfor preventing and/or treating uterine leiomyoma or other agents andalso have an excellent safety as medicine (or pharmaceuticalpreparation). The ulipristal acetate substance and the polymorphic formC of the invention are useful as contraceptive.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing an X-ray powder diffraction spectrum of acrystalline polymorphic form C of Example 1.

FIG. 2 is a graph showing a differential scanning calorimetry spectrumof the crystalline polymorphic form C of Example 1.

FIG. 3 is a graph showing an X-ray powder diffraction spectrum of acrystalline polymorphic form A of Example 2.

FIG. 4 is a graph showing a differential scanning calorimetry spectrumof the crystalline polymorphic form A of Example 2.

FIG. 5 is a graph showing an X-ray powder diffraction spectrum of acrystalline polymorphic form B of Example 3.

FIG. 6 is a graph showing a differential scanning calorimetry spectrumof the crystalline polymorphic form B of Example 3.

DESCRIPTION OF EMBODIMENTS

[Ulipristal acetate substance] As used herein, an ulipristal acetatesubstance refers to ulipristal acetate in the form of a mixture orcomposition of polymorphic forms. An ulipristal acetate substanceaccording to the invention comprises at least polymorphic form C. Insome embodiments, the ulipristal acetate substance according to theinvention comprises at least 5% by weight of the polymorphic form C, theweight percentage referring to the total weight of the ulipristalacetate substance.

As used herein, at least 5% by weight of the polymorphic form Cencompasses at least 10%, at least 20%, at least 30%, at least 40%, atleast 50%, at least 60%, at least 70% at least 80% at least 90% byweight of the polymorphic form C. In a preferred embodiment, thepolymorphic form C is the main polymorphic form of ulipristal acetatepresent within the ulipristal acetate substance of the invention. Thismeans that the ulipristal acetate substance of the invention comprisesno less than 50% by weight of polymorphic form C, preferably at least90%, more preferably at least 95%, and even more preferably at least99.5% by weight of polymorphic form C. The remaining polymorphic formspresent in the ulipristal acetate substance of the invention may be anamorphous form of ulipristal acetate or any crystalline forms ofulipristal acetate. In some embodiments, the ulipristal acetatesubstance of the invention essentially consists in polymorphic form C asdescribed herein.

The ulipristal acetate substance is characterized by a diffraction peakin X-ray powder diffraction pattern. Specifically, the ulipristalacetate substance contains at least a crystalline polymorphic form C ofulipristal acetate (crystal C) and has at least a diffraction patternderived from the crystalline polymorphic form C in an X-ray powderdiffraction spectrum.

The crystalline polymorphic form C has diffraction peaks at adiffraction angle 2theta of at least

9.0±0.2°, 9.3±0.2°, and 15.7±0.2°

in an X-ray powder diffraction spectrum. These diffraction peaks areusually ranked in the top three intensities in many cases. Thediffraction peak at

9.3±0.2°

may show the largest intensity. The preferred crystalline polymorphicform C has diffraction peaks at the following diffraction angle 2thetain an X-ray powder diffraction spectrum:

-   -   9.0±0.2°, 9.3±0.2°, 10.8±0.2°, 11.5±0.2°, 12.2±0.2°, 13.1±0.2°,        14.3±0.2°, 15.6±0.2°, 15.7±0.2°, 15.9±0.2°, 16.6±0.2°,        17.6±0.2°, 17.9±0.2°, 18.9±0.2°, 19.3±0.2°, and 23.8±0.2°.

In some embodiments, the crystalline form C of the invention has a X-raydiffraction pattern as depicted in FIG. 1 or as described in Table 1.

The X-ray powder diffraction spectrum can be measured according to acommon method, preferably using a diffractometer with Cu K alpha-1radiation source, for example, the condition of Examples mentionedbelow. The diffraction angle 2theta of the diffraction peak sometimesvaries within a range of about

±0.2° (e.g., about)±0.1°

depending on the measurement conditions and the state of samples.However, the same crystal structure has almost the same X-ray powderdiffraction pattern without significant change in the number ofcharacteristic diffraction peaks.

The ulipristal acetate substance is characterized by peak(s) in adifferential scanning calorimetry spectrum. Specifically, the ulipristalacetate substance has peak(s) derived from at least the crystallinepolymorphic form C in a differential scanning calorimetry spectrum.

The crystalline polymorphic form C may have an endothermic peak (ormelting point) at about 135 to 145° C. (e.g., about 137 to 143° C.,preferably about 139 to 141° C.) in the differential scanningcalorimetry spectrum. Moreover, the crystalline polymorphic form C mayhave an exothermic peak at about 145 to 170° C. (e.g., about 160 to 167°C., preferably about 163 to 165° C.). It is presumed that the exothermicpeak is a peak due to transition to the crystalline polymorphic form Afrom the crystalline polymorphic form C. Further, the crystallinepolymorphic form C may have an endothermic peak at about 180 to 192° C.and preferably about 183 to 190° C. It is presumed that the endothermicpeak is a peak due to melting of the transited crystalline polymorphicform A.

In some embodiments, the polymorphic form C of the invention hasdifferential scanning calorimetry spectrum as depicted in FIG. 2.

It is sufficient that the ulipristal acetate substance of the inventioncontains the crystalline polymorphic form C. The ulipristal acetatesubstance of the invention may further contain a different crystallineulipristal acetate (polymorphic crystal of ulipristal acetate). Theulipristal acetate substance of the invention may further containamorphous ulipristal acetate and/or a crystalline ulipristal acetatedistinct from form C. Examples of the different crystalline polymorphicform may include a crystalline polymorphic form having a diffractionpeak in diffraction angle range different from that in the crystallinepolymorphic form C in an X-ray powder diffraction spectrum, for example,

(1) a crystalline polymorphic form A (crystal A) of an ulipristalacetate having an X-ray powder diffraction spectrum comprisingdiffraction peaks at the following diffraction angle 2theta:

-   -   9.2±0.2°, 11.4±0.2°, 11.7±0.2°, 12.0±0.2°, 15.2±0.2°, 17.0±0.2°,        17.2±0.2°, and 24.4±0.2°;

and

(2) a crystalline polymorphic form B (crystal B) of an ulipristalacetate having an X-ray powder diffraction spectrum comprisingdiffraction peaks at the following diffraction angle 2theta:

-   -   6.4±0.2°, 8.4±0.2°, 9.4±0.2°, 9.6±0.2°, 11.8±0.2°, 12.8±0.2°,        15.3±0.2°, 16.7±0.2°, 17.5±0.2°, 18.6±0.2°, 19.3±0.2°,        21.0±0.2°, and 25.5±0.2°.

As the different crystalline polymorphic form, there may be mentioned acrystalline polymorphic form having an endothermic peak (or meltingpoint) in a temperature range different from that in the crystallinepolymorphic form C in a differential scanning calorimetry spectrum, forexample, a crystalline polymorphic form A having an endothermic peak (ormelting point) at about 180 to 192° C. (preferably about 183 to 190°C.), a crystalline polymorphic form B having an endothermic peak (ormelting point) at about 160 to 170° C. (e.g., about 165 to 169° C.,preferably about 166 to 168° C.).

For instance, the crystalline form A may have the X-ray powderdiffraction pattern as depicted in FIG. 3 or described in Table 2 and/orthe differential scanning calorimetry spectrum as shown in FIG. 4. Thecrystalline form B may have the X-ray powder diffraction pattern asshown in FIG. 5 or described in Table 3 and/or the differential scanningcalorimetry spectrum as shown in FIG. 6.

The different crystalline polymorphic forms may be used alone or incombination. Among the different crystalline polymorphic forms, thecrystalline polymorphic form B is preferred in terms of solubility.

The ratio (weight ratio) of the crystalline polymorphic form C relativeto the different crystalline polymorphic form (such as the crystallinepolymorphic form A or the crystalline polymorphic form B) is notparticularly limited to a specific one, and can be selected from therange of about 0.5/99.5 to 99.5/0.5 (e.g., about 1/99 to 99/1) in aratio of the former/the latter. For example, the ratio may be about10/90 to 99.5/0.5 (e.g., about 20/80 to 99.5/0.5), preferably about30/70 to 99/1 (e.g., about 40/60 to 99/1), and more preferably about50/50 to 99/1 (e.g., about 60/40 to 95/5, preferably about 70/30 to90/10).

The ulipristal acetate substance (ulipristal acetate mixture or mixedcrystal) containing the crystalline polymorphic form C and the differentcrystalline polymorphic form has structural characteristics derived fromthese respective crystalline forms (e.g., a diffraction peak in an X-raypowder diffraction spectrum, an endothermic peak in a differentialscanning calorimetry spectrum). Incidentally, the intensity ratio of thediffraction peaks (or the endothermic peaks) of these respectivecrystalline forms often corresponds to the mixing ratio of theserespective crystalline forms.

The ulipristal acetate substance (or each crystalline polymorphic form)may contain a low molecular weight compound (or a solvent) [or a lowmolecular weight compound (or a solvent) may adhere to the ulipristalacetate]. The low molecular weight compound (or the solvent) is notparticularly limited to a specific one as far as the low molecularweight compound (or the solvent) is pharmaceutically acceptable. Forexample, the low molecular weight compound (or the solvent) may includewater and an organic solvent [for example, an aliphatic hydrocarbon(e.g., hexane), an aromatic hydrocarbon (e.g., toluene), an alcohol(e.g., a C₁₋₄alkanol such as ethanol, 1-propanol, or isopropanol), anether (e.g., an acyclic ether such as diethyl ether; a cyclic ether suchas dioxane or tetrahydrofuran), a ketone (e.g., acetone and methyl ethylketone), an ester (e.g., a formate and an acetate), an amide (e.g.,dimethylformamide and dimethylacetamide), a sulfoxide (e.g.,dimethylsulfoxide), and a cyclic amine (e.g., pyridine)]. These lowmolecular weight compounds (or solvents) may be used alone or incombination. The amount of the low molecular weight compound (or theadhering amount thereof) relative to 100 parts by weight of theulipristal acetate (or each crystalline polymorphic form) may forexample be about not more than 30 parts by weight, preferably about notmore than 20 parts by weight, and more preferably about not more than 10parts by weight (e.g., about 0.001 to 1 parts by weight).

The ulipristal acetate substance (or each crystalline polymorphic form)may be a single crystal or may be a twin crystal or a polycrystal. Theform (external form) of the ulipristal acetate substance (or eachcrystalline polymorphic form) is not particularly limited to a specificone. For example, the form of the crystalline ulipristal acetate may betriclinic, monoclinic, rhombic (orthorhombic), tetragonal, cubic,trigonal (rhombohedral), hexagonal, or other forms. The crystallineulipristal acetate may be a spherulite, a skeleton crystal, a dendrite,a needle crystal (for example, a crystal whisker), or others.

The particle size of the ulipristal acetate substance or the polymorphicform C is not particularly limited to a specific one. For example, theaverage particle size (average particle diameter) of the ulipristalacetate substance or the polymorphic form C based on a laser diffractionmay be about 0.5 micrometers to 1 millimeter and preferably about 1 to500 micrometers (e.g., about 2 to 100 micrometers) or is usually about 5to 50 micrometers (e.g., about 5 to 30 micrometers). The ulipristalacetate substance or the polymorphic form C of the invention may bemicronized.

The ulipristal acetate substance or the polymorphic form C of theinvention is highly soluble in a solvent and has an excellentbioavailability. For example, the solubility of the ulipristal acetatesubstance or the polymorphic form C in a mixed solvent of ethanol andwater [ethanol/water (volume ratio)=10/90] may be about 7 to 30micrograms/mL, preferably about 8 to 27 micrograms/mL, and morepreferably about 9 to 25 micrograms/mL (e.g., about 10 to 25micrograms/mL) at 37° C.

[Process for producing ulipristal acetate substance or polymorphic formC] The process for producing the ulipristal acetate substance or thepolymorphic form C of the invention is not particularly limited to aspecific one as far as a crystal characterized by the above-mentionedX-ray powder diffraction spectrum or differential scanning calorimetryspectrum can be obtained. The process for producing the ulipristalacetate substance or the polymorphic form C of the invention comprises,for example, a step for dissolving an isopropanol-solvated crystal ofulipristal acetate in a mixed solvent containing ethanol and water andcrystallizing (precipitating or depositing) an ulipristal acetate fromthe solution (or crystallization system).

The isopropanol content (the degree of isopropanol solvation) of theisopropanol-solvated crystal of ulipristal acetate may for example beabout 0.5 to 5 mol, preferably about 0.5 to 2.5 mol, and more preferablyabout 0.5 to 1 mol (e.g., about 0.5 mol) relative to 1 mol of theulipristal acetate.

The isopropanol-solvated crystal of ulipristal acetate can be producedby a common method, for example, by allowing3,3-(1,2-ethanedioxy)-5alpha-hydroxy-11beta-(4-N,N-dimethylaminophenyl)-17alpha-acetoxy-19-norpregna-9-ene-20-oneto react with an acid (for example, an organic acid such as acetic acidor trifluoroacetic acid; and an inorganic acid such as hydrochloricacid, sulfuric acid, monopotassium sulfate, or phosphoric acid),dissolving the reaction mixture [or a crude purified product obtained bypurifying the reaction mixture with a common purification means (such asfiltration, centrifugation, chromatography, or recrystallization)] inisopropanol, and crystallizing an ulipristal acetate from the solution.In order to obtain the isopropanol-solvated crystal certainly, it ispreferable that the crystallization step be repeated a plurality oftimes (for example, twice to four times). The details of the productionprocess of the isopropanol-solvated crystal may for example be referredto Japanese Patent Application Laid-Open Publication No. 2006-515869, orothers.

In the mixed solvent, the ratio (volume ratio) of ethanol relative towater may for example be about 70/30 to 90/10, preferably about 72/28 to88/12, and more preferably about 75/25 to 85/15 in a ratio of theformer/the latter. The ratio of the mixed solvent relative to 1 g of theisopropanol-solvated crystal of ulipristal acetate may for example beabout 0.5 to 50 mL, preferably about 1 to 20 mL, and more preferablyabout 5 to 15 mL.

The method for crystallizing (recrystallizing or separating) anulipristal acetate from the solution (or crystallization system) mayinclude a cooling method (a method which comprises cooling acrystallization system), a poor-solvent addition method (a method whichcomprises adding a poor solvent for an ulipristal acetate to acrystallization system), and others. The preferred method includes thecooling method. For the cooling method, the cooling rate is notparticularly limited to a specific one. The cooling may be slow coolingor rapid cooling. The preferred cooling is slow cooling. For example,the cooling rate may for example be about 0.01 to 5° C./minute,preferably about 0.05 to 3° C./minute, and more preferably about 0.1 to1° C./minute.

In order to obtain the crystalline polymorphic form C withoutsubstantial coexistence with other crystalline forms in crystallization,it is preferable that a seed crystal be not added to the solution of theisopropanol-solvated crystal of ulipristal acetate (or thecrystallization system).

The step of dissolving the ulipristal acetate crystal in the mixedsolvent and crystallizing (or recrystallizing) the ulipristal acetatefrom the solution may be conducted repeatedly a plurality of times (forexample, twice to four times). Moreover, after crystallization (orrecrystallization), the resulting product may be dried (such as by airdrying, through circulation drying, or drying under a reduced pressure).The resulting product is usually dried under a reduced pressure [forexample, dried under not more than 50 hPa, preferably not more than 20hPa (e.g., about 1 to 15 hPa)]. The drying temperature may be a roomtemperature to a heated temperature, preferably about 25 to 120° C.(e.g., about 50 to 120° C.), and more preferably about 30 to 110° C.(e.g., about 80 to 110° C.). The drying time may for example be about 1to 24 hours (e.g., about 5 to 24 hours) and preferably about 1 to 20hours (e.g., about 10 to 20 hours).

According to the above-mentioned step, the crystalline polymorphic formC may be prepared as a single form.

A method for preparing an ulipristal acetate substance may comprise thesteps of:

-   -   a) providing the crystalline form C of the invention,    -   b) providing one or several polymorphic form(s) of ulipristal        acetate, and    -   c) mixing the crystalline form C with polymorphic form(s)        provided in step b.

In some embodiment, the method for preparing an ulipristal acetatesubstance may comprise the steps of forming the different crystallinepolymorphic form by crystallization or transition (transformation) inassociation with the solvent (precipitation from the solution,condensation of the solution, transition in the solution or dispersionmedium) and mixing the crystalline polymorphic form C and the differentcrystalline polymorphic form.

The raw ulipristal acetate to be subjected to the step for forming thedifferent crystalline polymorphic form may include the reaction mixture(or the crude purified product obtained by purifying the reactionmixture with a common purification means) as described in the productionprocess of the isopropanol-solvated crystal of ulipristal acetate, andothers.

The solvent (or crystallization solvent) may include water, an organicsolvent [for example, an aliphatic hydrocarbon (e.g., an acyclicaliphatic hydrocarbon such as hexane; and an alicyclic hydrocarbon suchas cyclohexane), an aromatic hydrocarbon (e.g., toluene), an alcohol(e.g., an C₁₋₄alkanol such as ethanol, 1-propanol, 2-propanol, or1-butanol), an ester (e.g., ethyl formate, ethyl acetate, isopropylacetate, and isobutyl acetate), a ketone (e.g., acetone and methyl ethylketone), an ether (e.g., an acyclic ether such as diethyl ether; and acyclic ether such as dioxane or tetrahydrofuran), a sulfoxide (e.g.,dimethylsulfoxide), an amide (e.g., an N-alkylacylamide such asN,N-dimethylformamide or N,N-dimethylacetamide), a nitrile (e.g., analkanenitrile such as acetonitrile), a cyclic amine (e.g., pyridine)],and others. These solvents may be used alone or in combination.

The ratio of the solvent relative to 1 g of the raw ulipristal acetatemay for example be about 0.1 to 500 mL, preferably about 0.5 to 400 mL,and more preferably about 1 to 300 mL (e.g., about 2 to 200 mL).

Examples of the method for forming the different crystalline polymorphicform may include a cooling method, a poor-solvent addition method, aseed crystal addition method (a method which comprises dissolving a rawulipristal acetate in a solvent and adding a seed crystal of ulipristalacetate to the solution), an evaporation method (a method whichcomprises dissolving a raw ulipristal acetate in a solvent andcondensing the solution), and a stir-suspension method (a method whichcomprises changing a crystalline form of an ulipristal acetate in astate that the ulipristal acetate is dispersed in a solvent).

Among the different crystalline polymorphic forms, the crystallinepolymorphic form A may for example be prepared by dissolving anisopropanol-solvated crystal of ulipristal acetate in a mixed solventcontaining ethanol and water and adding a seed crystal (crystallinepolymorphic form A or B) to the solution for crystallization. Moreover,the crystalline polymorphic form B may for example be prepared bydissolving the raw ulipristal acetate in ethanol and cooling (rapidlycooling) the solution, or may be prepared by dissolving the rawulipristal acetate in at least one solvent selected from the groupconsisting of ethanol, 1-propanol, and ethyl acetate and condensing thesolution.

Incidentally, in the mixed solvent containing ethanol and water used forthe production of the crystal A, the ratio (volume ratio) of ethanolrelative to water may for example be about 75/25 to 85/15 in a ratio ofthe former/the latter.

[Use and pharmaceutical composition] Since the crystalline form C or theulipristal acetate substance of the present invention has not only anantiprogestational activity but also an antiglucocorticoidal activity,the crystalline form C or the ulipristal acetate substance is preferablyused as a selective progesterone receptor modulator. Specifically, thecrystalline form C or the ulipristal acetate substance of the presentinvention is useful for preventing and/or treating of a gynecologicaldisease [for example, uterine leiomyoma or a disease attributable touterine leiomyoma (e.g., metastatic leiomyoma, dysmenorrhea,menorrhagia, anemia, infertility, constipation, pollakiuria, andlumbago)]. Moreover, the crystalline form C or the ulipristal acetatesubstance of the present invention is also useful as a contraceptiveagent, for example an emergency contraceptive agent.

The crystalline form C or the ulipristal acetate substance of theinvention may be also useful as a drug, for instance for treating and/orpreventing a gynecological disorder. As used herein, gynecologicaldisorders encompass, without being limited to, uterine fibroids orleiomyoma, endometriosis, uterine bleedings, pain associated withdislocation of endometrium and the like.

The invention also relates to a method for treating a female patientpreferably suffering from a gynecological disorder comprisingadministering a therapeutic effective amount of the crystalline form Cor that of the ulipristal acetate substance of the invention to saidpatient.

A further aspect of the invention is a method for providingcontraception to a woman in need thereof, comprising administering saidwoman with a contraceptive amount of the polymorphic form C or theulipristal acetate substance of the invention.

The contraceptive method of the invention may be an emergencycontraceptive method wherein the administration of the polymorphic formC or that of the ulipristal acetate substance of the invention occurswithin 120 hours after an unprotected intercourse. Alternatively, thecontraceptive method may be a regular contraceptive method wherein theadministration of ulipristal acetate is repeated several days in a rowwithin the menstrual cycle. Alternatively, the contraceptive method ofthe invention may be an on-demand contraception method as described inWO2010/119029, the disclosure of which being incorporated by reference.Preferably, the administration of ulipristal acetate in contraceptivemethods of the invention is oral.

The invention also relates to the use of the polymorphic form C or thatof the ulipristal acetate substance of the invention in the manufactureof a contraceptive or in the manufacture of a drug for treating agynecological disorder.

The above-mentioned crystalline form C or the ulipristal acetatesubstance may be used as a medicine alone, or the above-mentionedcrystalline form C or the ulipristal acetate substance may be used incombination with a carrier (e.g., a pharmacologically or physiologicallyacceptable carrier) to provide a pharmaceutical composition (or apreparation).

In a further aspect, the invention relates to a pharmaceuticalcomposition comprising the polymorphic form C or the ulipristal acetatesubstance of the invention and a pharmaceutically acceptable excipient.In some embodiments, the pharmaceutical composition of the invention issuch that at least 5% by total weight of the ulipristal acetate presentin the pharmaceutical composition is polymorphic form C. In some furtherembodiments, polymorphic form C is the main polymorphic form ofulipristal acetate present within the composition. This means that thepharmaceutical composition of the invention may comprise no less 50% ofpolymorphic form C with respect to total weight of ulipristal acetatepresent within the composition. In some embodiments polymorphic form Caccounts for at least 60%, preferably at least 80% and even at least 90%by weight with respect to the total weight of ulipristal acetate presentwithin the composition.

The pharmaceutical composition may comprise from 0.01% to 80% by weightof the polymorphic form C or the ulipristal acetate substance of theinvention and from 20% to 99.99% by weight of excipient(s).

With respect to the pharmaceutical composition of the present invention,the excipient(s) may be suitably selected depending on the form of thecomposition or preparation (that is, the dosage form), the route ofadministration, the application (or use), and others. The dosage form isnot particularly limited to a specific one and may be a solidpreparation (for example, powdered preparations, powders, granulatedpreparations (e.g., granules and microfine granules or the like),spherical or spheroidal preparations, pills, tablets, capsules(including soft capsules and hard capsules), dry syrups, andsuppositories), a semisolid preparation (for example, creams, ointments,gels, gumdrop-like preparations, and film-like preparations, sheet-likepreparations), a liquid preparation (for example, solutions,suspensions, emulsions, syrup, elixir, lotions, injectable solutions (orinjections), and drops), and others. Moreover, sprays or aerosols of thepowdered preparations and/or the liquid preparation may be alsoincluded. Incidentally, the capsules may be a capsule filled with aliquid or a capsule filled with a solid preparation (such as granules).Moreover, the preparation may be a lyophilized preparation. Further, thepreparation of the present invention may be a preparation releasing theactive ingredient(s) at a controlled rate (a sustained releasepreparation or a rapid-release preparation). Moreover, the preparationmay be an oral dosage form [for example, granules, powders, tablets(e.g., sublingual tablets and orally disintegrating tablets), capsules,syrup, emulsions, suspensions, jellys, gumdrop-like preparations, andfilm preparations] or a parenteral dosage form (for example, inhalants,preparations for transdermal administration, and preparations fortransnasal administration). Furthermore, the preparation may be topicalor local administration form [for example, injections (e.g., hypodermicinjections, intravenous injections, intramuscular injections, andintraabdominal injections), suspensions, ointments, plasters andpressure sensitive adhesives, cataplasms.

The excipient(s) may suitably be selected, for example, depending on theadministration route and the application of preparation, from components(e.g., a diluent, a binder, a disintegrant, a lubricant, and a coatingagent) listed in Japanese Pharmacopoeia, (1) Handbook of PharmaceuticalExcipients (Maruzen Company, ltd., (1989)), (2) Japanese PharmaceuticalExcipients Dictionary 2007 (Yakuji Nippo Ltd., issued July, 2007), (3)Pharmaceutics, revised fifth edition (Nankodo, Co., Ltd. (1997)), and(4) Japanese Pharmaceutical Excipients 2003 (Yakuji Nippo Ltd., issuedAugust, 2003). For example, the excipient for a solid preparation ispractically at least one member selected from the group consisting of adiluent, a binder, and a disintegrant. Moreover, the pharmaceuticalcomposition may contain a lipid.

The diluent may include a saccharide or a sugar alcohol such as lactose,glucose, sucrose, mannitol, sorbitol, or xylitol; a starch such as acorn starch; a polysaccharide such as a crystalline cellulose (includinga microcrystalline cellulose); silicon dioxide or a silicate such as alight silicic anhydride; and others. The binder may include a solublestarch such as a pregelatinized starch or a partially pregelatinizedstarch; a polysaccharide such as gum acacia (or gum arabic), dextrin, orsodium alginate; a synthetic polymer such as a polyvinylpyrrolidone(PVP), a polyvinyl alcohol (PVA), a carboxyvinyl polymer, a polyacrylicpolymer, a polylactic acid, or a polyethylene glycol; a cellulose ethersuch as a methyl cellulose (MC), an ethyl cellulose (EC), acarboxymethyl cellulose (CMC), a carboxymethyl cellulose sodium, ahydroxyethyl cellulose (HEC), a hydroxypropyl cellulose (HPC), or ahydroxypropylmethyl cellulose (HPMC); and others. The disintegrant mayinclude a sodium carboxymethyl starch, a carmellose, a carmellosesodium, a carmellose calcium, a croscarmellose sodium, a crospovidone, alow-substituted hydroxypropyl cellulose, and others. These excipientsmay be used alone or in combination.

The pharmaceutical composition may be a coated form. For example, theremay be used, as the coating agent, a saccharide or a sugar, a cellulosederivative such as an ethyl cellulose or a hydroxymethyl cellulose, apoly(oxyethylene glycol), a cellulose acetate phthalate, ahydroxypropylmethyl cellulose phthalate, a methylmethacrylate-(meth)acrylic acid copolymer, and eudragit (a copolymer ofmethacrylic acid and acrylic acid). The coating agent may be an entericcomponent (e.g., a cellulose phthalate, a hydroxypropylmethyl cellulosephthalate, and a methyl methacrylate-(meth)acrylic acid copolymer) or agastric soluble component comprising a polymer (e.g., eudragit)containing a basic component such as a dialky-laminoalkyl(meth)acrylate.Moreover, the preparation may be a capsule having such an entericcomponent or gastric soluble component as a capsule shell.Alternatively, the pharmaceutical composition may be a coated oruncoated tablet.

In the preparation, known additives can be suitably used depending on anadministration route, a dosage form, and others. Such an additive mayinclude, for example, a lubricant, a disintegrant aid, an antioxidationagent or an antioxidant, an emulsifier, a dispersing agent, a suspendingagent, a dissolving agent, a dissolution aid, a thickener, a pHadjusting agent or a buffer, a stabilizer, an antiseptic agent or apreservative, a fungicide or antibacterial agent, an antistatic agent, acorrigent or a masking agent, a coloring agent, a deodorant or aperfume, an algefacient, an antifoaming agent, an isotonizing agent, anda soothing agent. These additives may be used alone or in combination.

The pharmaceutical composition (or pharmaceutical preparation) of thepresent invention may contain other physiologically active components orpharmacologically active components (for example, a follicle hormone (oran estrogen preparation)) if necessary.

The pharmaceutical composition of the present invention may be preparedby using an excipient component in addition to an effective ingredient,and if necessary, an additive and the like, with a conventionalpreparation manner (for example, a production process described inJapanese Pharmacopoeia 16th edition or a process in accordance with theproduction process).

The pharmaceutical composition may comprise from 1 mg to 50 mg,preferably from 5 mg to 40 mg of ulipristal acetate per dosage unit, forinstance 5, 10, 15, 20 or 30 mg per dosage unit.

The crystalline form C or the ulipristal acetate substance of thepresent invention (also including the agent for preventing and/ortreating a gynecological disease, the contraceptive, and thepharmaceutical composition), which has a low toxicity and an excellentsafety, is safely administered to female human beings and non-humans,usually mammals (for example, human beings, mice, rats, rabbits, dogs,cats, bovines, horses, pigs, and monkeys). The amount to be administered(or dose) may be selected according to the species, age, body weight,and condition (e.g., a performance status, a condition of a disease, apresence of a complication) of the subject to be administered, theduration (or period or schedule) of administration, the dosage form, themethod (or route) of administration, and others. For example, the amountto be administered (or dose) to human beings (daily dose) is about 1 to50 mg/day and preferably about 5 to 40 mg/day.

The method (or route) of administration may be an oral administration ora local or parenteral administration (for example, hypodermicadministration, intravenous administration, intramuscularadministration, transrectal administration, and transvaginaladministration).

The frequency of administration is not particularly limited to aspecific one. For example, the frequency of administration may be once aday or if necessary may be a plurality times a day (e.g., twice to threetimes a day).

EXAMPLES

The following examples are intended to describe this invention infurther detail and should by no means be interpreted as defining thescope of the invention.

[X-ray powder diffraction spectrum] The X-ray powder diffractionspectrum was measured under the following conditions: radiation source:Cu K(alpha1), tube voltage: 40 kV, tube current: 40 mA, samplinginterval: 0.1°, scanning speed: 10°/minute. In the X-ray powderdiffraction chart, the diffraction peak was searched by second orderdifferential as a peak width threshold of 0.1°.

[Differential scanning calorimetry spectrum] The differential scanningcalorimetry spectrum was measured using a differential scanningcalorimeter (type: DSC8230L) at a rate of heating of 2° C./minute.

[Solubility] For each of ulipristal acetate samples obtained in Examplesand Comparative Example, the solubility was determined as follows. Theulipristal acetate (40 mg) was added to 40 mL of a mixed solventcontaining ethanol and water [ethanol/water (volume ratio)=10/90] havinga temperature of 37° C. to prepare a test sample. The test sample wasstirred by a magnetic stirrer for 5 minutes. Then a portion of thesuspension was separated. The solid of the separated portion wasfiltered out, and the ulipristal acetate content of the residue wasquantitatively determined using a high-performance liquid chromatography(column: ODS, column temperature: 40° C., eluate: 0.1% trifluoroaceticacid aqueous solution/acetonitrile mixture (volume ratio 3:2), rate offlow: 1.0 mL/minute, detection: UV 302 nm), and the solubility wascalculated.

[Absorption test in dog] For each of ulipristal acetate samples obtainedin Examples and Comparative Example, the absorption test was performedas follows. The ulipristal acetate was filled into a gelatin capsuleshell (manufacturer: Qualicaps Co., Ltd., size: No. 00, lot: C0079A) toproduce a capsule. The capsule was orally administered to 6 female dogsat a dose of 25 mg/kg (in terms of ulipristal acetate). The blood wascollected 0.5, 1, 2, 4, 6, 24, and 48 hours after the oraladministration. Then the sample was centrifuged to give a plasma. Theconcentration of the ulipristal acetate in the plasma was measured by aLC-MS/MS (liquid chromatography-tandem mass spectrometry) method, andthe elimination half-life (T₁₁₂), the time to the maximum plasmaconcentration (T_(max)), the maximum plasma concentration (C_(max)), thearea under the plasma concentration-time curve (AUC), and the meanresidence time (MRT) were calculated. The capsule was administered toeach female dog twice at dosing intervals (washout period) of one weekby crossover method.

COMPARATIVE EXAMPLE

38.5 g of3,3-(1,2-ethanedioxy)-5alpha-hydroxy-11beta-(4-N,N-dimethylaminophenyl)-17alpha-acetoxy-19-norpregna-9-ene-20-one[carbinol acetate] was loaded into a flask under nitrogen atmosphere ata temperature of 20 to 22° C., and 385 mL of deionized water and 17.91 gof potassium bisulfate were added. The obtained suspension was stirreduntil complete dissolution, for about 4 hours. The end of the reactionwas determined by means of thin layer chromatography (TLC).

To the reaction solution was added 3.85 g of neutral Al₂O₃, the mixturewas stirred for 30 minutes, the suspension was filtered and theinsoluble particles were washed with 38.5 mL of deionized water. To thefiltrate was added 325 mL of ethyl acetate, and the pH was adjusted to avalue between 7.0 to 7.2 with a 7% (w/v) sodium bi-carbonate solution.The mixture was allowed to stand for 15 minutes, the phases wereseparated, discharging the aqueous phase. To the resulting organic phasewas added 192.5 mL of deionized water, the mixture was stirred for 10minutes and then allowed to stand for 15 minutes. The phases wereseparated, discharging the aqueous phase.

The resulting organic phase was vacuum-concentrated to give a rawulipristal acetate residue. To the residue was added 38.5 mL ofisopropanol, and the mixture was vacuum-concentrated. To the resultingresidue was added the same amount (38.5 mL) of isopropanol, the mixturewas vacuum-concentrated again. To the resulting solid product was added77 mL of isopropanol, and the mixture was heated for dissolution. Thesolution was allowed to cool to 0 to 5° C., and the temperature wasmaintained for one hour. The obtained suspension was filtered and thecake was washed with cold isopropanol to give an isopropanol hemisolvatecrystal at a yield of 96% by mol.

By using the isopropanol hemisolvate crystal (10 g), an ulipristalacetate was crys-tallized in accordance with Japanese Patent ApplicationLaid-Open Publication No. 2006-515869 (JP-2006-515869A) to give 7.5 g ofa crystalline polymorphic form A of ulipristal acetate (crystal A),which had a melting point of 189° C.

Example 1

The ulipristal acetate crystal (1.761 g) obtained in Comparative Examplewas dissolved in 10 mL of isopropanol by heating, and the solvent wasdistilled off under a reduced pressure. The resulting residue wasdissolved in 9 mL of isopropanol by heating, and the solvent wasdistilled off under a reduced pressure. The resulting residue wasdissolved in 9 mL of isopropanol by heating, and the solution wasallowed to stand in ice-water bath for one hour. The precipitate wasseparated by filtration to give an ulipristal acetate isopropanolhemisolvate wet crystal (1.782 g). The wet crystal (1.782 g) wasdissolved in 17.8 mL of a mixed solvent containing ethanol and water[ethanol/water (volume ratio)=80/20] by heating, and the solution wasallowed to cool to a room temperature taking about one hour and stirredat a room temperature for 17 hours. The resulting precipitate wasseparated by filtration and dried for 19 hours at a temperature of 100°C. under a reduced pressure of not more than 15 hPa to give 1.0 g of acrystal C (crystalline polymorphic form C). The X-ray powder diffractionspectrum of the crystalline polymorphic form C is shown in FIG. 1, andthe differential scanning calorimetry spectrum thereof is shown in FIG.2. Moreover, the diffraction peak intensity and relative intensity ineach diffraction angle (grid interval d value) of the crystallinepolymorphic form C are shown in Table 1.

TABLE 1 Peak Peak search Relative number 2θ setting width d valueIntensity intensity 1 9.000 0.176 9.8176 496545 87 2 9.290 0.129 9.5118573438 100 3 9.660 0.141 9.1483 32155 6 4 10.760 0.141 8.2154 184379 335 11.460 0.129 7.7151 27227 5 6 12.230 0.153 7.2310 52258 10 7 13.0700.153 6.7681 34832 7 8 13.960 0.118 6.3386 31827 6 9 14.270 0.129 6.2016143850 26 10 15.550 0.129 5.6938 140981 25 11 15.730 0.106 5.6291 20708237 12 15.870 0.106 5.5797 180768 32 13 16.640 0.153 5.3232 199796 35 1417.640 0.153 5.0237 134958 24 15 17.910 0.176 4.9485 190161 34 16 18.3100.165 4.8413 48306 9 17 18.920 0.153 4.6866 134054 24 18 19.340 0.1534.5857 116322 21 19 20.000 0.129 4.4359 23063 5 20 20.940 0.165 4.238823052 5 21 22.840 0.141 3.8903 41340 8 22 23.290 0.129 3.8162 21740 4 2323.840 0.165 3.7293 78463 14 24 24.100 0.071 3.8897 21189 4 25 24.3000.118 3.6598 29305 6 26 24.880 0.153 3.5744 48228 9 27 25.540 0.1413.4848 39081 7 28 25.680 0.106 3.4662 20439 4 29 27.260 0.176 3.268735190 7 30 27.490 0.118 3.2419 28642 5

Example 2

The ulipristal acetate crystal (0.1 g) obtained in Comparative Exampleand the crystal C (0.1 g) obtained in Example 1 were mixed to give anulipristal acetate substance. The X-ray powder diffraction spectrum ofthe crystalline polymorphic form A is shown in FIG. 3, and thedifferential scanning calorimetry spectrum thereof is shown in FIG. 4.Moreover, the diffraction peak intensity and relative intensity in eachdiffraction angle (grid interval d value) of the crystalline polymorphicform A are shown in Table 2.

TABLE 2 Peak Peak search Relative number 2θ setting width d valueIntensity intensity 1 8.950 0.059 9.8723 117262 13 2 9.200 0.153 9.6046909978 100 3 11.420 0.129 7.7420 111952 13 4 11.700 0.118 7.5574 13859816 5 12.000 0.153 7.3691 64339 8 6 14.570 0.153 6.0745 32458 4 7 15.2300.141 5.8127 445131 49 8 15.730 0.059 5.6291 29270 4 9 15.920 0.1415.5623 99980 11 10 16.530 0.176 5.3584 97384 11 11 17.020 0.106 5.2052212875 24 12 17.210 0.106 5.1482 127643 15 13 17.410 0.141 5.0895 15174317 14 17.610 0.141 5.0321 54979 7 15 18.070 0.118 4.9051 63909 8 1618.340 0.129 4.8335 56374 7 17 19.070 0.165 4.6500 150154 17 18 20.4700.118 4.3351 62815 7 19 22.910 0.094 3.8786 19100 3 20 23.650 0.0713.7589 84081 10 21 23.890 0.118 3.7217 55242 7 22 24.140 0.071 3.683717902 2 23 24.350 0.118 3.6524 220346 25 24 24.780 0.071 3.5900 46366 625 26.530 0.141 3.3570 22271 3 26 27.650 0.141 3.2235 35719 4 27 32.6500.165 2.7404 24996 3 28 33.430 0.082 2.6782 18411 3 29 34.940 0.0822.5658 35439 4 30 35.030 0.059 2.5595 19308 3

Example 3

The ulipristal acetate crystal (1.3 g) obtained in Comparative Examplewas dissolved in 6.5 mL of ethanol by heating. The solution was allowedto stand at 26° C. for one hour and then at 4° C. for 16 hours. Theresulting precipitate was separated by filtration and dried under areduced pressure until the weight reached a constant value, and 1.0 g ofa crystal B was obtained. The crystal B (0.1 g) and the crystal C (0.1g) obtained in Example 1 were mixed to give an ulipristal acetatesubstance. The X-ray powder diffraction spectrum of the crystallinepolymorphic form B is shown in FIG. 5, and the differential scanningcalorimetry spectrum thereof is shown in FIG. 6. Moreover, thediffraction peak intensity and relative intensity in each diffractionangle (grid interval d value) of the crystalline polymorphic form B areshown in Table 3.

TABLE 3 Peak Peak search Relative number 2θ setting width d valueIntensity intensity 1 6.410 0.153 13.7775 123754 37 2 8.410 0.08210.5050 208444 62 3 8.990 0.071 9.8285 50955 16 4 9.160 0.059 9.646599364 30 5 9.350 0.141 9.4509 294241 87 6 9.640 0.153 9.1672 311885 93 711.790 0.141 7.4999 97918 29 8 12.750 0.165 6.9373 157752 47 9 13.3600.071 6.6219 41904 13 10 13.460 0.106 6.5729 38720 12 11 14.450 0.0826.1247 101060 30 12 14.530 0.094 6.0912 95603 29 13 15.260 0.129 5.8014126572 38 14 15.700 0.106 5.6398 34881 11 15 16.720 0.188 5.2979 18033754 16 17.280 0.129 5.1275 146882 44 17 17.470 0.106 5.0722 338814 100 1817.880 0.153 4.9568 31182 10 19 18.590 0.153 4.7690 284305 84 20 18.7300.059 4.7337 69226 21 21 18.920 0.082 4.6866 59328 18 22 19.340 0.1534.5857 72477 22 23 20.970 0.176 4.2328 126309 38 24 21.320 0.118 4.164134931 11 25 21.490 0.176 4.1316 44872 14 26 22.240 0.141 3.9939 30974 1027 24.130 0.129 3.6852 45421 14 28 25.530 0.165 3.4862 81415 25 2926.970 0.082 3.3032 28409 9 30 28.210 0.094 3.1608 37295 11

The results of Comparative Example and Examples are shown in Tables 4and 5.

TABLE 4 Comparative Example Example Example Example 1 2 3 Solubility 6.411.2 10.0 9.5 (μg/mL)

As apparent from Table 4, Examples 1 to 3 show significantly highsolubility and excellent bioavailability compared with ComparativeExample.

TABLE 5 Pharmacokinetic Comparative parameters Example Example 1 T_(1/2)(hr) 14.9 37.3 T_(max) (hr) 1.8 1.2 C_(max) (ng/mL) 1490.7 2200.2AUC_(0-t) (ng · hr/mL) 8447.4 12194.3 AUC_(0-inf) (ng · hr/mL) 9390.718078.4 MRT_(last) (hr) 11.8 11.7 MRT_(inf) (hr) 16.6 37.7

As apparent from Table 5, Example 1 is excellent in the respects of allof T_(max), C_(max), AUC_(0-t), AUC_(0-inf), and MRT_(last), comparedwith Comparative Example and shows excellent pharmacokinetics as apharmaceutical product which is quickly be absorbed into the body.

Preparation Example 1

A capsule was obtained by filling the crystal C obtained in Example 1into a capsule shell (Size 0).

Preparation Example 2

The crystal C obtained in Example 1 and carrier components were mixed inaccordance with the following formulation. The mixture was granulated bydry granulating and then sized to give a granule.

[Formulation]

Crystal C obtained in Example 1  300 mg Crystalline cellulose  590 mgSodium carboxymethyl starch  50 mg Glycerin fatty acid ester  50 mg Talc 10 mg Total amount 1000 mg

Preparation Example 3

The granule obtained in Preparation Example 2 and carrier componentswere mixed in accordance with the following formulation. The mixture wassubjected to tablet compression to give a tablet.

[Formulation]

Granule obtained in Preparation Example 2 100 mg Crystalline cellulose174 mg Glycerin fatty acid ester  20 mg Talc  4 mg Light silicicanhydride  2 mg Total amount 300 mg

Preparation Example 4

The tablet obtained in Preparation Example 3 was coated with a coatingagent having the following formulation to give a film-coated tablet.

[Formulation of coating agent]

Hypromellose 70.5% by weight Titanium oxide 20.5% by weight Propyleneglycol  6.9% by weight Iron sesquioxide  2.1% by weight

INDUSTRIAL APPLICABILITY

The crystalline polymorphic form of the ulipristal acetate or theulipristal acetate substance according to the present invention has anextremely high solubility and more excellent stability or absorptioncompared with a conventional crystalline form, and can improvebioavailability. Therefore, the crystalline polymorphic form or theulipristal acetate substance of the present invention is preferably usedas a selective progesterone receptor modulator. Moreover, thecrystalline polymorphic form or the ulipristal acetate substance of thepresent invention is useful for prevention and/or treatment of agynecological disease [for example, uterine leiomyoma or a diseaseattributable to uterine leiomyoma (e.g., metastatic leiomyoma,dysmenorrhea, menorrhagia, anemia, infertility, constipation,pollakiuria, and lumbago)]. Further, the crystalline polymorphic form orthe ulipristal acetate substance of the present invention is also usefulas an emergency contraceptive agent.

The invention claimed is:
 1. A crystalline polymorphic form C ofulipristal acetate having an X-ray powder diffraction pattern comprisingdiffraction peaks at the following diffraction 2theta angles: 9.0±0.2°,9.3±0.2°, 10.8±0.2°, 11.5±0.2°, 12.2±0.2°, 13.1±0.2°, 14.3±0.2°,15.6±0.2°, 15.7±0.2°, 15.9±0.2°, 16.6±0.2°, 17.6±0.2°, 17.9±0.2°,18.9±0.2°, 19.3±0.2°, and 23.8±0.2; wherein the crystalline polymorphicform C of ulipristal acetate has a differential scanning calorimetryspectrum comprising an endothermic peak at about 135 to 145° C.
 2. Aulipristal acetate substance comprising the crystalline polymorphic formC of ulipristal acetate recited in claim
 1. 3. The ulipristal acetatesubstance according to claim 2, which further comprises a crystallinepolymorphic form A of ulipristal acetate, wherein the crystallinepolymorphic form A has an X-ray powder diffraction pattern comprisingdiffraction peaks at the following diffraction 2theta angles: 9.2±0.2°,11.4±0.2°, 11.7±0.2°, 12.0±0.2°, 15.2±0.2°, 17.0±0.2°, 17.2±0.2°,24.4±0.2°.
 4. The ulipristal acetate substance according to claim 3,wherein the ratio of the crystalline polymorphic form C relative to thecrystalline polymorphic form A is 0.5/99.5 to 99.5/0.5 in a weight ratioof the former/the latter.
 5. The ulipristal acetate substance accordingto claim 2, which further contains a crystalline polymorphic form B ofulipristal acetate, wherein the crystalline polymorphic form B has anX-ray powder diffraction pattern comprising diffraction peaks at thefollowing diffraction 2theta angles: 6.4±0.2°, 8.4±0.2°, 9.4±0.2°,9.6±0.2°, 11.8±0.2°, 12.8±0.2°, 15.3±0.2°, 16.7±0.2°, 17.5±0.2°,18.6±0.2°, 19.3±0.2°, 21.0±0.2°, 25.5±0.2°.
 6. The ulipristal acetatesubstance according to claim 5, wherein the ratio of the crystallinepolymorphic form C relative to the crystalline polymorphic form 13 is0.5/99.5 to 99.5/0.5 in a weight ratio of the former/the latter.
 7. Apharmaceutical composition comprising the crystalline polymorphic form Cof ulipristal acetate recited in claim 1 or the ulipristal acetatesubstance recited in claim 2, and a pharmaceutically acceptableexcipient.
 8. A process for producing the crystalline polymorphic form Cof ulipristal acetate of claim 1, comprising: (a) providing anisopropanol-solvated crystal of ulipristal acetate; (b) dissolving theisopropanol-solvated crystal of ulipristal acetate by heating in a mixedsolvent containing ethanol and water at a volume ratio of about 75/25 toabout 85/15, wherein the amount of the isopropanol-solvated crystal ofulipristal acetate in the mixed solvent is 1 g of the crystal in about 5to 15 ml of the mixed solvent; (c) cooling the solution from step (b) toroom temperature with a cooling rate ranging from 0.05 to 3° C./minuteand stirring the solution at room temperature; (d) recovering ulipristalacetate product formed in step (c) and drying the ulipristal acetateproduct under a reduced pressure, at a temperature ranging from 80° C.to 110° C., for 5 to 24 hours; and (e) recovering crystallinepolymorphic form C of ulipristal acetate.
 9. The process according toclaim 8, carried out without addition of a seed crystal to the solution.10. A method for providing contraception or for treating uterinefibroids in a woman in need thereof, comprising administering aneffective amount of the crystalline polymorphic form C of ulipristalacetate recited in claim 1 or the ulipristal acetate substance recitedin claim 2.